Mannan-Binding Proteins (hereinafter simply referred to as “MBP” and sometimes called as Mannose-Binding Proteins, Mannose-Binding Lectin (MBL) or Mannan-Binding Lectin (MBL)). Conglutinin, Surfactant Protein A (SP-A) and Surfactant Protein D (SP-D), and each of them belongs to a group called as collectin.
With reference to FIG. 1, collectin comprises basic constituent unit having the four unique regions of (1) calcium ion (Ca2+)-dependent carbohydrate recognition domain (CRD), (2) neck region, (3) collagen-like region and (4) N-terminal region containing cystein [Malhotra et al., European Journal of Immunology, Vol. 22, pp. 1437-1445 (1992)], then triple helix are formed by twisting three constituent units (three units) at each of their collagen-like region, and subunits are formed.
Such subunits may further constitute oligomer structure like trimer, tetramer or hexamer. Of the collectins, MBP is specifically binding to Mannose or N-Acetyl-Glucosamine and needs calcium (ion) for such binding, for example, form of MBP from the human serum is homopolymer having, as the constituent units, the subunits in the molecular weight of about 32,000 Da [Teizo Fujita, “Complement Activation and Lectin Pathway”, Rinsho-Meneki, Vol. 29, No. 3, pp. 405-410 (1997)].
In vertebrates, mechanisms involving specific antibody reaction and immune response through the cells are considered as a main host-defense system against inversion of the pathogenic bacteria. However, recently, non-specific immune response by these lectins seems that it may play an important role to neutralize and remove the various microorganisms and virus in the puerile subjects having the maternal transmigration antibody and the undeveloped specific defense system [Super et al., Lancet, Vol. II, pp. 1236-1239 (1989): Nobutaka Wakamiya, Yasuhiko Suzuki, “Anti-Viral activity by Collectin” Rinsho-Meneki, Vol. 29, No. 4, pp. 508-513 (1997)].
Then, regarding the role of these lectins on biological defense in host organism, it is reported that infection will be easily spread by, for example, the reduction of MBP concentration in blood due to the genetic mutation of MBP gene [Sumiya et al. Lancet, Vol. 337, pp. 1569-1570 (1991)].
The present inventor once reported that the conglutinin and MBP inhibit infection and hemaggulutination inhibition activities of H1 and H3 Type Influenza A Viruses [Wakamiya et al. Glycoconjugate Journal, Vol. 8, p. 235 (1991); Wakamiya et al., Biochem. Biophys. Res. Comm., Vol. 187, pp. 1270-1278 (1992)].
In particular, with respect to the human MBP (hereinafter simply referred to as “hMBP”), many aspects including their structure and their physiological functions (activities) have recently been investigated eagerly. For example, Ezekowitz et al., reported the analysis results on the hMBP structure as their structure and their gene [Epstein et al. “The collectins in innate immunity”, Current Opinion in Immunology, Vol. 8, pp. 29-35, (1996); Japanese Patent Translation Publication No. 2-504581]
On the other hand, as an aspect on biological-function of hMBP, hMBP have been considered that it involves with basal immunity like (i) anti-microbial activities, (ii) opsonin activities, (iii) complement activation [Kazuhide Uemura, et al., “Correlation between Structure and Function of Calcium Dependence Animal Lectin on Host Defence”, Jikken-Igaku, Vol. 13, No. 18 (1995)]. With respect to an clinical application, in view of the findings obtained through analysis on deficit of MBP in blood, it had also been reported that cause of such deficit is gene mutation in collagen-like structure and, thereby, amino acids mutation, and, accordingly, both stabilities of MBP itself and MBP concentration in blood were reduced [Sumiya et al., “Mannose-binding protein, genetic variants and the risk of infection”, Q. J. Med., No. 89. pp. 723-726 (1996); Thomas et al., “Mutation of gene for mannose-binding protein associated with chronic hepatitis B viral infection”, The Lancet, Vol. 348, pp. 1417-1419 (1996); Ezekowitz, “Mannose-binding protein and susceptibility to chronic hepatitis B infection”, The Lancet, Vol. 348, pp. 1396-1397 (1996)].
Also, it had been reported that MBP concentration in blood is concerned with a pathogenicity of hepatitis B viral and HIV infection. In contrast thereto, it has also been suggested that MBP may involve with lectin pathway through MBP, due to abnormalities on sugar chain of immunoglobulin, in the disorder like chronical rheumatoid arthritis [Malbotra et al., “Glycosylation changes of IgG associated with rheumatoid arthritis can activate complement via the mannose-binding protein”, Nature Medicine, Vol. 1, pp. 237-243 (1995)] or IgA nephrosis [Mitsuhiro Matsuda et al., “Involvement of Mannan Binding Protein with crisis and progression of IgA nephrosis”, Journal of Nephrology Association of Japan, vol. 39, No. 3, p. 235 (1997)]
Further, according to the recent studies, it had also been reported that, besides the susceptibility to HIV by hMBP, it may involve with latency prior to crisis of AIDS (Acquired Immuno Deficiency Syndrome), hMBP may therefore contribute to prolong the life of AIDS patients [Garred, et al., “Susceptibility to HIV infection and progression of AIDS in relation to variant alleles of mannose-binding lectin”, The Lancet, Vol. 349, pp. 236-240 (1997)].
Unfortunately, although utilities of hMBP as physiologically active medical materials (components) have been expected, since the source of which is depended on the animal serum like human or rabbit serum, continuous production thereof was quite difficult and the yield thereof was very small. Further, artificial large scale production system for hMBP by gene recombination techniques have not yet been established.